Trimethylamine N-oxide impairs β-cell function and glucose tolerance.
Lijuan KongQijin ZhaoXiaojing JiangJinping HuQian JiangLi ShengXiaohong PengShu-Sen WangYibing ChenYanjun WanShaocong HouXing-Feng LiuChunxiao MaYan LiLi QuanLiangyi ChenBing CuiPing-Ping LiPublished in: Nature communications (2024)
β-Cell dysfunction and β-cell loss are hallmarks of type 2 diabetes (T2D). Here, we found that trimethylamine N-oxide (TMAO) at a similar concentration to that found in diabetes could directly decrease glucose-stimulated insulin secretion (GSIS) in MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels impairs GSIS, β-cell proportion, and glucose tolerance in male C57BL/6 J mice. TMAO inhibits calcium transients through NLRP3 inflammasome-related cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on β-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes β-cell ER stress, dedifferentiation, and apoptosis and inhibits β-cell transcriptional identity. Inhibition of TMAO production improves β-cell GSIS, β-cell proportion, and glucose tolerance in both male db/db and choline diet-fed mice. These observations identify a role for TMAO in β-cell dysfunction and maintenance, and inhibition of TMAO could be an approach for the treatment of T2D.
Keyphrases
- single cell
- cell therapy
- type diabetes
- stem cells
- gene expression
- physical activity
- nlrp inflammasome
- weight loss
- cardiovascular disease
- adipose tissue
- cell proliferation
- blood pressure
- cell death
- insulin resistance
- cell cycle arrest
- bone marrow
- signaling pathway
- wild type
- diabetic rats
- combination therapy
- pi k akt
- high glucose